Biosynthesis of the bacterial antibiotic 3,7-dihydroxytropolone through enzymatic salvaging of catabolic shunt products
Abstract: The non-benzenoid aromatic tropone ring is a structural motif of numerous microbial and plant natural products with potent bioactivities. In bacteria, tropone biosynthesis involves early steps of the widespread CoA-dependent phenylacetic acid (paa) catabolon, from which a shunt product is sequestered and surprisingly further utilized as a universal precursor for structurally and functionally diverse tropone derivatives such as tropodithietic acid or (hydroxy)tropolones. Here, we elucidate the biosynthesis of the antibiotic 3,7-dihydroxytropolone in Actinobacteria by in vitro pathway reconstitution using paa catabolic enzymes as well as dedicated downstream tailoring enzymes, including a thioesterase (TrlF) and two flavoprotein monooxygenases (TrlCD and TrlE). We furthermore mechanistically and structurally characterize the multifunctional key enzyme TrlE, which mediates an unanticipated ipso-substitution involving a hydroxylation and subsequent decarboxylation of the CoA-freed side chain, followed by ring oxidation to afford tropolone. This study showcases a remarkably efficient strategy for 3,7-dihydroxytropolone biosynthesis and illuminates the functions of the involved biosynthetic enzymes
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Chemical science. - 15, 20 (2024) , 7749-7756, ISSN: 2041-6539
- Event
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Veröffentlichung
- (where)
-
Freiburg
- (who)
-
Universität
- (when)
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2024
- Creator
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Höing, Lars
Sowa, Sven T.
Toplak, Marina
Reinhardt, Jakob K.
Jakob, Roman
Maier, Timm
Lill, Markus A.
Teufel, Robin
- DOI
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10.1039/d4sc01715c
- URN
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urn:nbn:de:bsz:25-freidok-2472910
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:56 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Höing, Lars
- Sowa, Sven T.
- Toplak, Marina
- Reinhardt, Jakob K.
- Jakob, Roman
- Maier, Timm
- Lill, Markus A.
- Teufel, Robin
- Universität
Time of origin
- 2024
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Catabolic flexibility of mammalian-associated lactobacilli
Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis
Intermediates and shunt products of massiliachelin biosynthesis in Massilia sp. NR 4-1
Lsp family proteins regulate antibiotic biosynthesis in Lysobacter enzymogenes OH11
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Manipulation of glycopeptide antibiotic biosynthesis
Acute catabolic state
Enzymatic one-step ring contraction for quinolone biosynthesis
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